Label update but not prescribing restrictions warranted for saxagliptin and alogliptin, advisers say.

An FDA advisory committee urged new labeling information to warn about heart failure risk with saxagliptin (Onglyza) and still-unclear risk with alogliptin (Nesina).

All but one of 15 members of the agency's Endocrinologic and Metabolic Drugs Advisory Committee voting on saxagliptin said that evidence of increased risk of heart failure and all-cause mortality from a large trial warranted label revisions, to spell out those risks.

But 13 voted that, overall, the DPP-4 inhibitor has an acceptable cardiovascular risk profile under the FDA's standard and should not face additional restrictions on prescribing.

One committee member said she found the results from SAVOR "disturbing," even though they might have been due to chance in the large trial and might not constitute an actual increase from taking drug. But the general consensus of other members committee was they were not greatly concerned over the findings.

"[Saxagliptin] clearly, by any analysis, met the standard that was set at the beginning," said Erica Brittain, PhD, a researcher at the National Institute of Health and a committee member. "But overall, it was also pretty disappointing," she said, referring to the results of the SAVOR trial.

A rival diabetes drug, alogliptin, was also on trial Tuesday. The committee, with one additional voting member, was unanimous in finding that the drug had an acceptable risk profile. Thirteen of 16 voted to recommend new label language to reflect postmarketing trial findings that appeared equivocal on whether it increases heart failure risk.

Saxagliptin

Saxagliptin was the first diabetes drug to pass the FDA's cardiovascular safety review, in 2009, but the FDA required AstraZeneca to conduct long-term postmarketing studies. The results from the SAVOR trial, with more than 16,000 patients, were published in the New England Journal of Medicinein 2013. All patients in the trial had diabetes and more than 80% had cardiovascular risk factors.

SAVOR found that while the overall trial results did not reveal higher rates of a composite of adverse cardiovascular outcomes, it did show a greater risk of all-cause mortality with saxagliptin. In addition, those on the drug faced a greater risk of hospitalization for heart failure than did a group on placebo -- 3.5% of those in the saxagliptin group versus 2.8% in the placebo group (hazard ratio 1.27; 95% CI 1.07-1.51; P=0.007).

The FDA announced in early 2014 that they were investigating the link between heart failure and saxagliptin. Ever since the debacle of rosiglitazone (Avandia), the agency has required that applicants of new diabetic medications show that the product will not result in an "unacceptable increase of cardiovascular risk" -- with an the upper bound to the 1-sided 95% confidence interval for the estimated risk ratio less than 1.3.

Robert Smith, MD, a professor of medicine at Brown University and the chairperson of the committee, said that though he voted in favor of a label change for saxagliptin, it's not clear exactly how those changes should be made. "I do think there are challenges in how to handle the labeling in connecting it to the actual data," he said.

In a press release, AstraZeneca wrote that they are looking into the heightened risk of heart disease. "AstraZeneca will also conduct further investigation to better understand the signal of hospitalization for heart failure found in the SAVOR results," the firm noted.

Bonnie Arkus, RN, president of the Women's Heart Foundation and the acting consumer representative on the committee, was the only member who said that saxagliptin has an unacceptable cardiovascular risk profile. "It's just too much risk to take this step for a consumer," she said during her comment.

She also voted for withdrawing saxagliptin from the market entirely, noting that she did not see any of the benefits of the drug.

At the meeting Tuesday, risk of pancreatitis and renal failure for patients on saxagliptin was also discussed, but most of the panel said that they were only mildly concerned over renal failure risk, and that the results from SAVOR were still too preliminary.

Many of the committee members also noted that the findings might not be generalizable to all patients on saxagliptin, since SAVOR looked mostly at those already at an increased risk for heart disease.

Alogliptin

Alogliptin, also a DPP-4 inhibitor, was approved in 2013 in the U.S., with the subsequent EXAMINE trial comparing alogliptin to placebo. It did not find any significant differences in major outcomes between the two groups.

There was some confusion about how to interpret the data, especially given such a short follow-up time and a relatively small cohort of patients from the U.S., but the committee generally had only limited concern over the results of the trial.

William Hiatt, MD, a professor of medicine at the University of Colorado School of Medicine and a committee member, said that he found the EXAMINE results for heart failure reassuring. "I'm not sure that more exposure would elucidate this risk much more, and I'm not terribly concerned that this drug is associated with a significant risk of heart failure," he said.

Hiatt added that there's still a lack of certainty around some of the risks from taking alogliptin, particularly for those with renal impairment. Unlike SAVOR, EXAMINE included patients with renal impairment at baseline. Hiatt said that some of the confusion may be cleared up with different trial designs in the future.

The committee was split three to 13 over whether to put information about the trial in the labeling. Nearly all of the members said that the data for renal and heart failure was preliminary, but most thought the information still belonged on the label.

Gregory McIntyre, a patient representative on the committee, said that, "Any potential risk is worth noting," after voting for a label change.

Thomas Wang, MD, at the Vanderbilt University Medical Center, who voted against a label change, said he hopes "the committee continues to pay close attention to this."

And Anne Leddy, MD, an endocrinologist at the Gloucester-Mathews Free Clinic in Virginia, speaking on behalf of the American Association of Clinical Endocrinologists, said that the group will "await with interest recommendations or warnings."

"There is great need for new drugs to help manage the ever increasing burden of type 2 diabetes," said Leddy. "We need more effective medication to improve glycemic control for our patients without the risks of hypoglycemia and weight gain."

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